Therapeutic S1P Drug Targets for Cranial Bone Repair

颅骨修复的治疗性 S1P 药物靶点

• 批准号: 8069853
• 负责人: Edward A. Botchwey
• 金额: $ 34.77万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069853
• 关键词: 3-Dimensional; Adhesions; Affinity; Agonist; Animals; Attenuated; Autocrine Communication; Biocompatible Materials; Biological; Biological Assay; Blood Circulation; Blood Vessels; Bone Growth; Bone Regeneration; Calvaria; Cell Adhesion; Cell Communication; Cells; Cephalic; Chimera organism; Chronic; Clinical; Cutaneous; Data; Defect; Development; Dorsal; Dorsal Skinfold Window Chamber Model; Dose; Drug Delivery Systems; Encapsulated; Endothelial Cells; Endothelium; Family; Figs - dietary; G-Protein-Coupled Receptors; Glycolates; Growth; Harvest; Healed; Homing; Immunohistochemistry; Implant; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Kinetics; Label; Left; Leukocytes; Life Expectancy; Lipids; Marrow; Measures; Medical; Mesenchymal Stem Cells; Methods; Microspheres; Modeling; Mus; Natural regeneration; Oral; Organ; Organ Transplantation; Osteoblasts; Osteoclasts; Osteogenesis; Osteoid; Outcome; Paracrine Communication; Pathologic; Patients; Pericytes; Pharmaceutical Preparations; Population; Rattus; Receptor Signaling; Recombinants; Regulation; Relative (related person); Resolution; Role; Signal Transduction; Site; Smooth Muscle Myocytes; Stem cells; Supporting Cell; TNF gene; Tail; Testing; Therapeutic; Tissue Engineering; Tissue Grafts; Tissues; Transplantation; Veins; Waiting Lists; Wound Healing; angiogenesis; base; biodegradable polymer; bone; bone cell; bone healing; clinical application; craniofacial; cytokine; density; edg-3 Protein; gain of function; healing; implantation; in vivo; inflammatory modulation; inorganic phosphate; loss of function; migration; monocyte; osteoblast differentiation; osteoprogenitor cell; prevent; progenitor; public health relevance; receptor; reconstruction; research study; response; restoration; scaffold; skeletal injury; tissue regeneration; tomography

DESCRIPTION (provided by applicant): Sphingosine1-phosphate (S1P) is a pleiotropic autocrine and paracrine signaling small lipid molecule that directs a wide range of biological responses through a family of high-affinity G protein-coupled receptors (S1P1-S1P5). The proposed studies will interrogate the cooperative functions of S1P1 and S1P3 subtype activation in the microvasculature to promote inflammation resolution and bone repair. Although monocyte recruitment is a critical component of the normal bone healing cascade, persistent monocyte accumulation can progress into chronic inflammation and impede recruitment and differentiation of osteoblastic progenitor cells required for tissue regeneration. Preliminary studies show that S1P1 antagonizes pathologic inflammation by preventing monocyte adhesion to activated endothelium, and that sustained delivery of receptor selective drugs targeting S1P1 and S1P3 subtypes from 3-D biodegradable polymers promotes microvascular network maturation and increases osseous tissue ingrowth in critical sized cranial bone defects. Thus, the overarching hypothesis of this proposal is that sustained delivery of pharmacological agonists targeting S1P1 and S1P3 from biodegradable polymers promotes osseous defect healing by locally suppressing monocyte accumulation to tissue implants and promoting recruitment of mesenchymal progenitor cells (MPCs) to regenerate bone. AIM 1 will test the hypothesis that S1P1 and S1P3 act synergistically to promote mesenchymal stem cell adhesion to endothelium. AIM 2 tests the hypothesis that selective stimulation of S1P1/S1P3 from synthetic degradable polymers prevents local accumulation of monocytes and promotes homing of mesenchymal progenitor cells in a cutaneous model of chronic inflammation. AIM 3 tests the hypothesis that S1P1 and S1P3 modulation of inflammatory and mesenchymal progenitor cell recruitment will enhance bone healing outcomes. PUBLIC HEALTH RELEVANCE: The replacement or restoration of function to traumatized, damaged, or lost organs and tissues is an increasingly significant clinical problem. It is estimated that only 24,422 received organ transplants of a possible 79,512 patients on the transplantation wait list in 2002. In addition, it is currently estimated that over 1.5 million skeletal injuries alone will require tissue graft reconstruction in the US each year, and these numbers will continue to grow as the life expectancy of the population increases. Thus, the development of effective strategies to harness inflammation for revascularization and regeneration of osseous tissue defects is a significant medical need.

描述（由申请人提供）：鞘氨酸1-磷酸盐（S1P）是一种多效性自分泌和旁分泌信号传导小脂质分子，它通过高亲和力G蛋白偶联受体（S1P1-S1P5）来指导广泛的生物学反应（S1P1-S1P5）。拟议的研究将询问微脉管系统中S1P1和S13亚型激活的合作功能，以促进炎症分辨率和骨修复。尽管单核细胞募集是正常骨愈合级联反应的关键组成部分，但持续的单核细胞积累可以发展为慢性炎症，并阻碍组织再生所需的成骨细胞祖细胞的募集和分化。初步研究表明，S1P1通过防止单核细胞粘附对激活的内皮拮抗病理炎症，并且靶向S1P1和S1P3亚型的受体选择性药物的持续递送，从3-D生物降解的聚合物中均可促进微动网络网络摩托学和骨间骨骼的骨骼构成骨骼的骨骼较大的骨骼孔。因此，该提案的总体假设是，靶向S1P1和S13的药理学激动剂从可生物降解的聚合物中的持续递送通过将单核细胞积聚到组织植入物并促进间充质祖细胞（MPCS）到降低骨头，从而促进骨缺陷愈合。 AIM 1将检验以下假设：S1P1和S13协同作用以促进间充质干细胞对内皮的粘附。 AIM 2检验了以下假设：从合成降解聚合物中选择性刺激S1P1/S13可防止单核细胞的局部积累，并促进慢性炎症模型中间充质祖细胞的寄养。 AIM 3检验了炎症和间质祖细胞募集的S1P1和S13调节的假设将增强骨骼愈合结果。 公共卫生相关性：替代或恢复功能以创伤，损坏或丢失的器官和组织是一个越来越重大的临床问题。据估计，在2002年移植等待名单上，只有24,422例对79,512例患者进行了器官移植。此外，目前估计，仅150万骨骼损伤就需要每年在美国的组织移植物重建，并且这些人数将继续增长，因为人口的预期寿命会增加。因此，制定有效的策略来利用炎症，以进行骨组织缺陷的血运重建和再生。